According to the Asthma and Allergy Foundation of America and the National Pharmaceutical Council, an estimated 17 million Americans currently suffer from asthma. It is the most common chronic childhood disease, affecting more than one child in 20, nearly 5 million children in all, and it is the only chronic disease, besides AIDS and tuberculosis, with an increasing death rate. Each year over 5,000 Americans die from asthma.
The annual cost of asthma in 1998 was estimated to be $11.3 billion. Direct costs accounted for $7.5 billion and indirect costs were $3.8 billion. Hospitalizations accounted for the single largest portion of the cost and amount to nearly a half million hospitalizations, 1.6 million emergency room visits, and over 10 million office visits. Clearly there is a great need for new methods of treating the condition.
As discussed by Elias et al. (1999), J. Clin. Inv., 104(8):1001-1006, the effects of airway remodeling in the development of asthma were previously unknown as the condition was thought to be an entirely reversible disorder. More recent investigations have revealed, however, that significant airway remodeling occurs during asthma and that the degree of this remodeling is usually proportional to symptom severity. Remodeling typically takes the form of airway wall thickening, the development of subepithelial fibrosis, increased myocyte muscle mass, myofibroblast hyperplasia, and mucus metaplasia. Airway remodeling is also a common factor in the progression of chronic obstructive pulmonary disorder (COPD), and pulmonary fibrosis. Pulmonary inflammation is also a common component in the development of airway remodeling and may be typified by bronchiolitis, alveolitis, and/or vasculitis.
The correlation between airway remodeling and asthma presents a new avenue of asthma research. Recently the ability of cortical steroids and leukotrine receptor antagonists to prevent or treat airway remodeling has been reported (see Hoshino (2004) Clin Rev Allergy Immunol. 27(1):59-64). Given the potential negative side effects of long term treatment with cortical steroids and the uncertainties regarding the efficacy of leukotrine receptor antagonists, the exists a strong need for other methods of inhibiting airway remodeling.
Adenosine is known to play a role in asthma and COPD (See, Spicuzza et al. (2003) TiPS 24(8):409-4130; Mann et al, (1986) J Appl Physiol 61:1667-1676; and Feoktistov et al, (1998) Trends Pharmacol Sci 19:148-153.) The clinical evidence supporting the involvement of adenosine includes:                1) Plasma concentrations of adenosine are increased by allergen challenge in asthmatic patients and adenosine levels in the bronchoalveolar lavage fluid are elevated in asthmatic and COPD patients (Driver et al, (1993). Am Rev Respir Dis 148:91-97)        2) Adenosine (given as AMP) induces bronchoconstriction in asthmatics but not in normal subjects (Cushley et al, (1983) Br J Clin Pharmacol 15:161-165), and it increases the concentrations of mediators released from mast cells, such as histamine, tryptase, LTC4 and PDG2 (Crimi et al, (1997) Allergy 52:48-54). The adenosine-induced bronchoconstriction is attenuated by drugs that either inhibit mast cell activation or serve as antagonists to the mediators released from the mast cells. Thus, the potential mechanism of adenosine-induced bronchoconstriction is likely due to its effect on mast cell activation (Polosa et al, (2002) Thorax 57:649-654 and Polosa (2002) Eur Respir J 20:488-496.).        3) Adenosine has also been shown to induce eosinophilia and inflammation. The overall effects and potential clinical utilities of AMP-challenge are summarized in a recent review article by Spicuzza and Polosa, (2003) Curr Opin Allergy Clin Immunol 3:65-69.        
Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A1, A2A, A2B, and A3, all of which modulate important physiological processes. Of the various receptors, A2B adenosine receptors are believed to be most significantly involved in asthma via their connection to mast cell activation, vasodilation, and regulation of cell growth (See Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153). Specifically, adenosine A2B receptor antagonists have been shown to affect the activation of mast cell and have thus been implicated in the inhibition of the acute airway hyperresponsiveness. Surprisingly, it has now been found that A2B adenosine receptor antagonists are also useful in the prevention of airway remodeling and pulmonary inflammation.
Accordingly, it is desired to provide a method of preventing airway remodeling and/or pulmonary inflammation by administration of compounds that are potent, fully or partially selective, A2B antagonists, i.e., compounds that inhibit the A2B adenosine receptor.